title: The impact of inflammatory licensing on heme oxygenase-1-mediated induction of regulatory T cells by human mesenchymal stem cells.
abstract: Mesenchymal stem cells (MSCs) are characterized by their manifold immunomodulatory and regenerative properties. The stress-responsive, cytoprotective, and immunoregulatory molecule heme oxygenase-1 (HO-1) was recently identified as a key contributor for MSC-mediated suppression of alloactivated T cells. As HO-1 has also been implicated in the induction of regulatory T cells (Tregs), we sought to examine its impact on MSC-driven promotion of Tregs. Human MSCs were shown to induce, in a HO-1-dependent fashion, IL-10(+) Tr1 and transforming growth factor-β(+) Th3 Treg-subsets in allo- and T-cell receptor-activated lymphocytes. Because inflammatory stimuli modulate ("license") human MSCs, we were interested in whether an in vitro alloreactive micro-milieu within mixed lymphocyte reactions (MLRs) alters the HO-1 expression. We observed a substantial down-regulation of HO-1 facilitated by yet unidentified soluble factor(s) produced in an MLR, and most probably occurring at the level of its major transcription-factor NF-E2-related factor 2. Interestingly, HO-1 lost its impact regarding suppressiveness, Treg induction, and promotion of IL-10 production for MSCs, which were prelicensed in an MLR environment. Taken together, we show that HO-1 produced by human MSCs beyond its direct suppressive function promotes formation of Tr1 and Th3 Tregs and IL-10 production, functions, which are taken over by other molecules, among them COX-2, after an alloreactive priming.
authors.affiliation: Karolinska University Hospital Huddinge, Stockholm, Sweden. Dimitrios.Mougiakakos@ki.se
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Mougiakakos
authors.forename: Regina
authors.initials: R
authors.lastname: Jitschin
authors.forename: C Christian
authors.initials: CC
authors.lastname: Johansson
authors.forename: Riki
authors.initials: R
authors.lastname: Okita
authors.forename: Rolf
authors.initials: R
authors.lastname: Kiessling
authors.forename: Katarina
authors.initials: K
authors.lastname: Le Blanc
mesh_terms: D001483:Base Sequence; D017077:Culture Media, Conditioned; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007155:Immunologic Factors / Q000378:metabolism; D066298:In Vitro Techniques; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D007959:Lymphocyte Culture Test, Mixed; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D011994:Recombinant Proteins; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D017931:DNA Primers; D007155:Immunologic Factors; D011994:Recombinant Proteins; D007371:Interferon-gamma; D051547:Heme Oxygenase-1